ACS Medicinal Chemistry Letters最新文献_第6页

Novel Imidazo[4,5-c]pyridine Compounds as TLR7 Agonists for Treating Cancer.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00616

Ram W Sabnis

引用次数: 0

Novel Imidazo[4,5-c]pyridine Compounds as TLR7 Agonists for Treating Cancer

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 DOI: 10.1021/acsmedchemlett.4c0061610.1021/acsmedchemlett.4c00616

Ram W. Sabnis*,

引用次数: 0

Novel Pyridine Derivatives as 5-HT2A Agonists for Treating Psychiatric Disorders

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 DOI: 10.1021/acsmedchemlett.4c0062910.1021/acsmedchemlett.4c00629

Ram W. Sabnis*, and , Anika R. Sabnis,

引用次数: 0

Clozapine as an E3 Ligand for PROTAC Technology.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00500

Reina Takano, Nobumichi Ohoka, Takashi Kurohara, Noriaki Arakawa, Kenji Ohgane, Takao Inoue, Hidetomo Yokoo, Yosuke Demizu

{"title":"Clozapine as an E3 Ligand for PROTAC Technology.","authors":"Reina Takano, Nobumichi Ohoka, Takashi Kurohara, Noriaki Arakawa, Kenji Ohgane, Takao Inoue, Hidetomo Yokoo, Yosuke Demizu","doi":"10.1021/acsmedchemlett.4c00500","DOIUrl":"10.1021/acsmedchemlett.4c00500","url":null,"abstract":"New ubiquitin ligase (E3) ligands are crucial for developing proteolysis-targeting chimeras (PROTACs) to induce the degradation of a target protein. In this study, we developed a PROTAC using the antipsychotic drug clozapine as a new E3 ligand. First, a clozapine PROTAC targeting a model target HaloTag protein (Halo-PEG-Clozapine) was synthesized, and the PROTAC induced degradation of the HaloTag-fused protein in a cell culture system. Another clozapine PROTAC targeting the cancer therapeutic target estrogen receptor α (ERα) (Tamoxifen-PEG-Clozapine) was synthesized and induced degradation of the ERα protein in MCF-7 breast cancer cells. Experiments with inhibitors and siRNAs showed that Tamoxifen-PEG-Clozapine degraded ERα via a ubiquitin-proteasome system that uses the ubiquitin protein ligase E3 component N-recognin 5. These results indicate that clozapine is a promising E3 ligand that may expand the molecular design of PROTACs, contributing to the advancement of drug discovery by facilitating the degradation of disease-related proteins.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"258-262"},"PeriodicalIF":3.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel 6-Substituted-3-Phenylisoindolin-1-ones as Cbl-B Inhibitors for Treating Cancer

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 DOI: 10.1021/acsmedchemlett.4c0062810.1021/acsmedchemlett.4c00628

Ram W. Sabnis*,

引用次数: 0

Discovery of First-in-Class BAZ2A/B and BAZ2B-Selective Degraders

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-07 DOI: 10.1021/acsmedchemlett.4c0033410.1021/acsmedchemlett.4c00334

Leonardo Palaferri, Iván Cheng-Sánchez, Katherine Gosselé, Dominika Zielinska and Cristina Nevado*,

{"title":"Discovery of First-in-Class BAZ2A/B and BAZ2B-Selective Degraders","authors":"Leonardo Palaferri, Iván Cheng-Sánchez, Katherine Gosselé, Dominika Zielinska and Cristina Nevado*, ","doi":"10.1021/acsmedchemlett.4c0033410.1021/acsmedchemlett.4c00334","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00334https://doi.org/10.1021/acsmedchemlett.4c00334","url":null,"abstract":"Bromodomain adjacent to zinc finger 2A and 2B (BAZ2A and BAZ2B) are homologous proteins that serve as regulatory subunits in different initiation switch complexes. Despite their structural similarity, BAZ2A/B seem to play different roles in disease development. However, reported BAZ2A/B inhibitors bind similarly to both homologues. Here we report the discovery of dBAZ2 and dBAZ2B, first-in-class Proteolysis Targeting Chimeras (PROTACs) degrading BAZ2A/B and BAZ2B, respectively. dBAZ2 induces BAZ2A/B degradation with a Dmax ≥ 97% (BAZ2A_DC50 = 180 nM; BAZ2B_DC50 = 250 nM), while dBAZ2B selectively degrades BAZ2B with a DC50 = 19 nM and Dmax ≥ 97%. Degradation by dBAZ2 and dBAZ2B is almost complete within 2 h, is maintained for at least 3 days, and occurs in PC3 and MM1S cells, demonstrating the potential of these compounds as chemical probes to decipher the distinct biological functions of BAZ2A/B.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"234–240 234–240"},"PeriodicalIF":3.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of First-in-Class BAZ2A/B and BAZ2B-Selective Degraders.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-07 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00334

Leonardo Palaferri, Iván Cheng-Sánchez, Katherine Gosselé, Dominika Zielinska, Cristina Nevado

引用次数: 0

Exploring Arylidene–Indolinone Ligands of Autophagy Proteins LC3B and GABARAP

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI: 10.1021/acsmedchemlett.4c0051710.1021/acsmedchemlett.4c00517

Alexandria N. Leveille, Thomas Schwarzrock, Hawley Brown, Bennett True, Joanet Plasencia, Philipp Neudecker, Alina Üffing, Oliver H. Weiergräber, Dieter Willbold and Joshua A. Kritzer*,

{"title":"Exploring Arylidene–Indolinone Ligands of Autophagy Proteins LC3B and GABARAP","authors":"Alexandria N. Leveille, Thomas Schwarzrock, Hawley Brown, Bennett True, Joanet Plasencia, Philipp Neudecker, Alina Üffing, Oliver H. Weiergräber, Dieter Willbold and Joshua A. Kritzer*, ","doi":"10.1021/acsmedchemlett.4c0051710.1021/acsmedchemlett.4c00517","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00517https://doi.org/10.1021/acsmedchemlett.4c00517","url":null,"abstract":"We report the first structure–activity studies of arylidene–indolinone compound GW5074, which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound, and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP. Eighteen analogs were synthesized and tested against both proteins. Inhibitory potencies were found to be in the mid- to high-micromolar range. 2D-NMR data revealed the binding site on GABARAP as hydrophobic pocket 1, where native peptide ligands bind with an aromatic side chain. Our results suggest that GW5074 binds LC3B and GABARAP with micromolar affinity. These affinities could support further exploration in targeted protein degradation, but only if off-target effects and poor solubility can be appropriately addressed.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"271–277 271–277"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Imaging Alpha-synuclein with Novel 5H-Imidazo[1,5-b][1,2,4]triazole Radioligands for the Diagnosis of Parkinson’s Disease

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI: 10.1021/acsmedchemlett.4c0060710.1021/acsmedchemlett.4c00607

Zhendong Song, and , Steven H. Liang*,

引用次数: 0

Erratum: Addition to "The Death of the Strategy of Classical Chiral Switches Is an Exaggeration".

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00613

Israel Agranat, Ilaria D'Acquarica

引用次数: 0